1. Field of the Invention
The invention relates to methods of treating mast cell disease.
2. Description of the Prior Art
Mast cell disease is manifested in two, somewhat related conditions: urticaria pigmentosa and systemic mastocytosis.
Urticaria pigmentosa usually begins in early childhood and disappears partially or completely by adolescence. Characteristic skin lesions are single or multiple pigmented macules or nodules that urticate on rubbing and contain large numbers of mast cells.
Although uncommon, the disorder is seen in most dermatologic and pediatric practices. Light-skinned persons are affected most often, and it is slightly more common in males. The disorder has been reported in a parent and child in several families and in both members of monozygotic twins. More than 10 percent of cases are present at birth; over half develop by six months; and the majority appear before puberty. Onset after puberty raises the question of systemic mastocytosis.
Conventional treatments for urticaria pigmentosa have been relatively ineffective. Antihistamines may attenuate some of the symptoms, but aspirin and codeine degranulate mast cells and may aggravate symptoms. Although the disease is generally benign, in rare instances patients have developed serious complications such as infected bullae, peptic ulcers and bleeding tendencies.
Systemic mastocytosis, a rare, recently recognized disease, is being reported with increasing frequency. It affects both males and females and usually begins in adult life. The cause is unknown. The clinical manifestations and course may resemble those of lymphoma or leukemia, and it seems likely that the disorder should be classified with the reticuloendothelioses.
Skin or mucous membrane lesions may resemble childhood urticaria pigmentosa, but significant differences that indicate systemic mastocytoses are (1) onset after puberty, (2) multiple, small, confluent macules with persistent telangiectasia, (3) papules and nodules resembling leukemia cutis, (4) chronic lichenified dermatitis, (5) generalized infiltration of skin with a "scotch-grain" appearance, (6) less pigmentation, (7) less tendency to redden and urticate on stroking, (8) extensive involvement of oral, nasal, or rectal mucosa, and (9) progressive cutaneous change.
Histamine release into the general circulation is less likely than in childhood urticaria pigmentosa, yet patients may have flushing, shocklike episodes, and increased histamine in the urine. Diarrhea is often a prominent feature, and peptic ulcer occasionally develops.
The prognosis varies with the form of the disorder. Disease confined to skin and bone is compatible with long life and little morbidity, but there is always the threat of extension of the morbid process. Extensive reticuloendothelial involvement results in death in a few months to several years. Patients die from pancytopenia, infection, hemorrhage, cachexia, gastroenteritis, perforated peptic ulcer, and leukemia.
Conventional therapy is palliative and symptomatic and includes transfusions, antimicrobials, antihistamines, adrenal steroids, corticotrophin, roentgen irradiation, and nitrogen mustard.
Nalmefene (6-methylene-6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphine) is a long-acting, orally available, potent narcotic antagonist with pure antagonist activity. Apart from its utility in antagonizing the sedation, respiratory depression and other actions of opioid agents, nalmefene has also been found useful in treating diverse conditions such as hyperkinesia in children (U.S. Pat. No. 4,454,142), senile dementia (U.S. Pat. No. 4,511,570), sudden infant death syndrome (U.S. Pat. No. 4,639,455), autoimmune diseases (U.S. Pat. No. 4,857,533), arthritic and inflammatory diseases (U.S. Pat. No. 4,863,928), interstitial cystitis (U.S. Pat. No. 4,877,791), allergic rhinitis (U.S. Pat. No. 4,880,813). In commonly owned U.S. Pat. No. 4,923,875, the present inventor disclosed the utility of topical nalmefene in treating urticaria, various eczemas, and other mast cell-mediated dermatological disorders, but not the use of oral nalmefene in systemic mast cell disease. In commonly owned, published PCT Application No. US86/02268, it was disclosed that nalmefene is useful for the treatment of antigen-induced allergic responses, including those where degranulation of mast cells may be a causative factor.
Naltrexone (N-cyclopropylmethyl-14-hydroxydihydromorphinone) is another orally available narcotic antagonist with pure antagonist activity. Naltrexone has additionally been disclosed as useful for inducing anorexia (U.S. Pat. Nos. 4,477,457; 4,478,840) and for treating shock (U.S. Pat Nos. 4,267,182; 4,434,168), as well as for certain of the conditions cited above where nalmefene has been found useful.
In U.S. Pat. Nos. 4,877,791 and 4,923,875 it is disclosed that pure narcotic antagonists such as nalmefene and naltrexone may suppress histamine release from mast cells found in the bladder walls and the skin.
There does not currently exist any modality of drug treatment for mast cell disease, particularly systemic mastocytosis, which is known to be safe and effective in a significant number of cases.